Systemic lupus erythematosus (SLE) is an autoimmune disease clinically characterized by a waxing and waning course and by involvement of multiple organs including skin, kidneys and central nervous system (Kammer G M and Tsokos G C Eds. (1999) Lupus: Molecular and Cellular Pathogenesis 1st Ed, Human Press, N.J.; Lahita R G Ed. (1999) Systemic Lupus Erythromatosus, 3rd Ed, Academic Press, Amsterdams. The overall prevalence of SLE is about one in 2000, and about one in 700 Caucasian women develops SLE during her life time. Lahita R G (1999) supra. In the United States alone, over half a million people have SLE, and most are women in their childbearing years (Hardin J A (2003) J. Exp. Med. 185:1101-1111).
There is no single criteria to diagnose SLE. The American College of Rheumatology has developed 11 criteria to diagnose SLE, which span the clinical spectrum of SLE in aspects of skin, systemic, and laboratory tests. These criteria include malar rash, discoid rash, sensitivity to sun light, oral ulcers, arthritis, serositis, kidney and central nervous system inflammation, blood alterations, and the presence of antinuclear antibodies. A patient must meet four of these criteria in order to be classified as a SLE patient. (Tan et al. (1982) Arthritis Rheumatol. 25:1271-1277, the contents of which are incorporated by reference.) SLE is usually confirmed by tests including, but not limited to, blood tests to detect anti-nuclear antibodies; blood and urine tests to assess kidney function; complement tests to detect the presence of low levels of complement that are often associated with SLE; a sedimentation rate (ESR) or C-reactive protein (CRP) to measure inflammation levels; X-rays to assess lung damage and EKGs to assess heart damage.
Designing successful randomized controlled trials in SLE poses many challenges because it is a relapsing, remitting disease, with multiorgan system involvement ranging from mild to life threatening manifestations. While it is possible to identify serologic and immunologic abnormalities which characterize active disease, it has not previously been possible to treat expectantly, nor to initiate prophylactic, potentially preventative interventions on the basis of these markers. In addition, it has been difficult to correlate alterations in biologic markers with clinical outcome, especially when signs and symptoms are intermittent and broadly variable between patients. Accordingly, it would be useful to be able correlate gene expression profiles with prognosis and efficacy of therapeutic intervention.
The applicants generated previously expression profiles of SLE patients and controls using microarray technology. In the prior studies, it was found that 210 genes were up-regulated and 141 genes were down-regulated when PBMCs were isolated from 30 pediatric SLE patients (an auto-immune disease) as compared to healthy controls and patients with juvenile chronic arthritis (an auto-inflammatory disease). Fourteen of 15 genes showing the greatest differential expression were interferon (IFN) regulated (Bennett et al. (2003) J. Exp. Med. 197:711-723). Baechler et al. (2003 Proc. Natl. Acad. Sci. USA 100:2610-2615 and U.S. 2004/0033498), identified 161 genes, 23 of which are IFN-inducible, that were differentially expressed by at least 1.5 fold in peripheral blood mononuclear cells (PBMCs) isolated from 48 adult SLE patients compared to healthy adult controls. The IFN gene expression signature in SLE patients was correlated with disease severity. However, neither of these studies examined correlations between gene expression and the likelihood to develop renal disease in SLE patients.
The standard therapy for SLE is administration of the steroid glucocorticoid, a general immune response inhibitor. It can be used to relieve symptoms; however, no cure for SLE is currently available. Low dose p.o. prednisone at a level less than 0.5 mg/kg/day is usually given. Unfortunately, this therapy is insufficient to keep children in remission, and flaring of the disease is frequent. Flares can be controlled with high dose glucocorticoid via intravenous pulses at 30 mg methylprednisolone/kg/day for 3 consecutive days. However, steroid treatment at high dosage can present severe side effects for patients, especially pediatric patients.
Up to 25% of all SLE cases start before the age of 18 years. Children with SLE typically have more severe symptoms. Approximately 70% of pediatric SLE patients develop kidney involvement leading to renal failure, and 18% of children with SLE progress towards death. Lahita R G (1999) supra. Because pediatric SLE patients may develop life-threatening renal involvement, they are often treated aggressively with steroids, resulting in harmful or unwanted side effects which are typically more serious in children than in adults. Accordingly, the ability to predict the likelihood that an individual patient will develop renal disease would make it possible to reduce the dose of steroids or other treatments in those children who are unlikely to develop renal involvement, or to tailor other treatment plans according to the predicted outcome. Therefore, there is an unmet and urgent medical need for diagnostic methods that will predict the likelihood of renal involvement, as well as to diagnose SLE, distinguish SLE gene expression profiles from profiles of patients infected with influenza, and to monitor disease progression and treatment. This invention satisfies these needs and provides related advantages as well.